The major important developments in our recent glycolipid studies supported by this grant are: (1) increasing evidence has been provided that gangliosides, particularly GM[unreadable]3[unreadable] and GM[unreadable]1[unreadable], are involved in regulating cell proliferation through interaction with membrane receptors for fibroblast growth factors (FGF), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF). Defective synthesis of GM[unreadable]3[unreadable] or GM[unreadable]1[unreadable] as has been found in many transformed cells may be related to the loss of cell growth regulation through dysfunction of growth factor receptors; (2) some gangliosides, such as GM[unreadable]3[unreadable], GD[unreadable]1a[unreadable], and GM[unreadable]1[unreadable], have been found in the detergent-insoluble cell adhesion matrix, although the chemical quantity of total cellular gangliosides is decreased significantly. Therefore, a specific functional role of gangliosides in defining cell adhesion and changes in such a ganglioside function in the adhesion matrix of transformed cells are expected; and (3) a close correlation between ceramide composition, carbohydrate structure, and glycolipid antigenicity has been demonstrated. In view of these developments, we plan to study the following: (1) the mechanism for functional control of growth factor receptors via gangliosides, particularly a specific role of gangliosides in inducing conformational change of receptors through gangliosides; (2) the association of gangliosides in cell adhesion sites by comparison of increasing numbers of normal and transformed cells. Organization of glycolipids in the adhesion substratum will be studied by cross-linking reagents and with antibodies directed to gangliosides, adhesive proteins, and cytoskeletal components; and (3) the correlation between ceramide and the activity and organization of glycosyltransferases as well as the antigenicity of glycolipids. A comparative study of the possible role of ceramide in the antigenicity of glycolipids in normal and transformed cells is also planned. (A)